1. Field of the Invention
The invention relates to the field of implantable drug delivery systems, specifically a magnetically controlled aspirating pump and a method for delivering the anti-angiogenesis agent Bevacizumab (Avastin) into a brain tumor using the same.
2. Description of the Prior Art
When tumors develop inside the human body, the options for available treatment are fairly narrow. This is even more so when the tumor develops inside a vital organ such as the brain. Diseases such as brain cancer, i.e. malignant gliomas, and other cancers that develop in or around the brain are notoriously difficult to treat and thus have a high mortality rate. The invention described herein is directed specifically for malignant gliomas; however, it is applicable to all types of malignant tumors where local control is desired with direct intratumoral treatment with Avastin.
Traditionally, the options for treating a tumor located in or on the brain include surgery, radiation, chemotherapy, and local intratumoral therapy. Each of these prior methods of treating a brain tumor have had some form of success in the past, however each of them also contain various deficiencies and pitfalls that make them less than ideal when treating a patient. What is needed is a more reliable, easier, and effective process for treating a malignant brain tumor.
The oldest and most direct way for treating a brain tumor is to remove it surgically. Surgery is effective in obtaining tissue diagnosis and removing the mass effect of the tumor from the adjacent normal brain. However, it is invasive, expensive, and poses potential surgical complications for the patient. Most importantly, surgery cannot cure a malignant brain tumor, as the cancer cells have often invaded far into the normal brain when the diagnosis is first confirmed. Additionally, surgery is only available when the tumor is in a surgically accessible location. Tumors located deep within the brain are often inoperable as the surgery would significantly impair the patient's neurological function. Even if surgery is possible, there is still a chance of brain damage and an extremely long recovery time associated with surgery.
Radiation is the next mode of treatment for brain cancer. It is usually given as a fractionated dosage treatment, covering a certain field encompassing the tumor, over a period of six weeks. Spatially localized forms of radiation, including cyberknife and gamma knife have been used with varying levels of success. Although radiation is still widely acknowledged as the most effective mode of adjunctive treatment for a malignant brain tumor, it suffers from the disadvantage of limited fractions and applications, as the brain can only be radiated so much without developing severe sequelae.
The third method used to combat brain tumors is systemic chemotherapy. Systemic chemotherapy is a viable option as an adjunct to radiation and surgery. However, it is limited in efficacy in brain cancers by: 1) delivery across the blood brain barrier, 2) development of drug resistance by the cancer cells, and 3) systemic side-effects from the chemotherapeutic agent. Because the blood brain barrier is only partially broken down in the presence of a malignant brain tumor, it still impairs the effective delivery and transport of systemic chemotherapy into the brain cancer. Secondly, brain tumors can develop drug resistance. As a result, the cancer learns how to avoid cytotoxicity of the delivered drug. Lastly, chemotherapy is distributed systemically throughout the entire body. Because the whole body of the patient undergoes the treatment (not just the tumor and the tumor related area), undesirable side effects such as nausea, diarrhea, hair loss, and loss of appetite and energy may occur. Some of the side effects are so strong in some patients that chemotherapy is unavailable to them as a treatment and thus decrease their overall chances for survival.
The anti-angiogenesis agent Avastin is currently FDA approved for the treatment of recurrent glioblastoma multiforme (GBM). It is an antibody which is capable of binding to vascular endothelial growth factor (VEGF), the angiogenesis agent secreted by glioma cells, and is responsible for binding to the endothelial cells in the glioma, causing the blood vessels to proliferate and vascularize the glioma. It is currently administered via intravenous administration every two weeks, and is given as a stand-alone drug. No clear benefit has been documented for combination of Avastin with standard cytotoxic chemotherapy ie irinotecan (CPT-11). Because of the anti-angiogenesis nature of Avastin, it would be more effective when given on a continuous metronomic delivery. However, because of its need for intravenous administration, it is impossible to deliver it on a continuous basis. Moreover, because Avastin is an antibody, it is not capable of effectively crossing the blood brain barrier. Instead, it only binds to the VEGF present in the luminal side of the blood vessel. Intravenous Avastin is associated with a number of systemic side-effects including poor wound healing, deep venous thrombosis, renal toxicity, and threat of intracerebral hemorrhage. On the other hand, intratumoral Avastin would not be affected by these systemic complications, including poor wound healing.
The last major method of treating brain tumors has been the application of various local intratumoral therapies. These therapies include chemotherapy wafers, stereotactic injections, and convection enhanced deliveries. All of these treatment therapies involve directly infusing the tumor with an appropriate drug regimen; however this method too is not without its limitations. Chemotherapy wafers (Gliadel) are currently limited by only one drug available (BCNU), and by its diffusion capability of only a few millimeters away from the tumor bed. Stereotactic injections of chemotherapy have also been applied. However, only one injection is available at any single time. If another injection is needed, then another stereotactic surgical injection would have to be performed. Moreover, the spread of the chemotherapy is limited to the injection site and some of the adjacent normal brain. Lastly, convection enhanced delivery via an external micropump has been used to increase the circumference of drug delivery. It is usually given by an externalized catheter, and the drug is delivered for a cycle of 4-6 days. At the end of that time, the catheter will have to be removed. If the drug is to be delivered again, another surgical procedure for convection enhanced delivery will have to be performed. This can be very expensive and painful as some intratumoral therapies involve exposing the brain to an externalized catheter for long periods of time or complicated implantations of temporary catheters and other medical devices. Additionally, many of the previous intratumoral therapies are ineffective and do not significantly enhance or lengthen the life of a patient receiving such treatment.
The underlying hypothesis of using polypharmacy employed by the current invention is based on the premise that combination therapy is often better than monotherapy. Thus, a first step in administrating a cytotoxic agent is to determine the maximum tolerated dose (MTD). However, when used in traditional treatment mores, such as chemotherapy, the cytotoxic agents are delivered to the patient in a manner that allows the cytotoxic agents to be distributed more or less globally throughout the body of the patient. Relatively large doses of the drugs are required since only a small fraction of the administered dose will be present at the tumor site at any given time. The remainder of the dose will be in the other parts of body. Moreover, a major problem with conventional chemotherapy is lack of specificity in targeting the cancer cell.
The use of large doses of toxic agents often leads to serious and debilitating side effects. Moreover, the global administration of drugs is often not compatible with combination therapies where a number of medicating agents are used synergistically to treat tumors or other conditions. Thus, the global administration of medicating agents to treat tumors and other such medical conditions is an inefficient and often dangerous technique that often leads to severe or debilitating side effects.
The use of intratumoral Avastin has never been used in the human population. Considerations of intracerebral hemorrhage and lack of an effective delivery device have been factors inhibiting its use. From a treatment standpoint, intratumoral Avastin does have the advantage of continuous metronomic delivery, delivery to the glioma cells that are actually secreting VEGF (not just the luminal side of the blood vessel as in intravenous delivery), and potentially much lower amounts of Avastin needed to be effective. Recent experiments performed demonstrated that Avastin does not induce an intracerebral or intratumoral hemorrhage when administered intratumorally in an intracranial rodent model. Moreover, there was no increased evidence of an immune response from infusion of an antibody such as Avastin. Most importantly, we demonstrated that the survival time of these animals was significantly prolonged with intratumoral Avastin compared to intravenous Avastin as seen in FIG. 18.
Local administration of an anti-VEGF antibody has been employed by Roche (formerly Avastin) for macular degeneration. Studies have shown that it may be administered safely locally. However, intratumoral delivery of Avastin has never been shown in either in-vivo animal studies or human studies.
Recently, there have been some developments in the field of medical drug delivery systems. The majority of these systems have taken the form of a pump or other device that releases a variety of drugs into various positions in and around the body of a patient.
For example, many of the devices found in the prior art are much like the inventions disclosed in U.S. Pat. No. 6,852,104 (“Blonquist”) and U.S. Pat. No. 6,659,978 (“Kasuga”). Both of these inventions comprise a small tank for holding a drug regimen, a pump for pumping the drug regimen into the body of a patient, and some sort of electronic control system that allows the user to program the specific amount and at what time a certain drug regiment is to be administered. While these apparatus may be ideal for administering certain drugs such as insulin to patients who are diabetic, they are neither designed nor suitable for directly treating a tumor within the brain of a patient.
Other prior art examples such as U.S. Pat. No. 5,242,406 (“Gross”) and U.S. Pat. No. 6,571,125 (“Thompson”) offer smaller, more convenient alternatives for administering drugs, however their reliance on maintaining a specific set of pressures and a certain amount of electrical current respectively makes them too complicated and prone to error.
U.S. Pat. No. 7,351,239 (“Gill”), U.S. Pat. No. 7,288,085 (“Olsen”), and U.S. Pat. No. 6,726,678 (“Nelson”) disclose a pump or reservoir that is capable of delivering medicating fluids to the brain, but requires that the pump and drug reservoir be implanted in different locations within the patient. This configuration is not only uncomfortable for the patient, but also increases the possibility of infection and unnecessarily complicates the implanting procedure. Additionally, every time the patient needs the drug reservoir refilled or the pump battery replaced, the physician must invasively re-enter the patient. Finally, none these prior methods disclose a way of measuring the value of the vascular endothelial growth factor (VEGF) so as to enable tailoring of the delivered medical agent, toxicity to meet the needs of a specific individual patient.
What is needed is a device and a method that is capable of delivering medicating agents directly to a tumor located in the brain of a patient that is easy to operate and relatively simple to implant, while at the same time, is easy to maintain throughout the patient's treatment cycle and customize to the patient's specific needs without causing all of the negative side effects associated with previous treatment methods.
The combination of Avastin with the MBP allows for an unique combination of drug and device, enabling a new combination to be used in the treatment of malignant gliomas.